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000303645 1001_ $$00009-0002-4777-5922$$aSchubert, Annika$$b0
000303645 245__ $$aTargeting hypoxia-inducible factor-1 in a hypoxidative stress model protects retinal pigment epithelium cells from cell death and metabolic dysregulation.
000303645 260__ $$aLondon$$bNature Publishing Group$$c2025
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000303645 520__ $$aOxidative stress and hypoxia lead to dysfunction of retinal pigment epithelium (RPE) cells and are hallmarks of diseases such as age-related macular degeneration (AMD), the most common blinding disease in the elderly population. We have previously shown that a combination of these two risk factors, i.e. hypoxidative stress, exacerbates RPE cell death by ferroptosis. Hypoxia leads to stabilization of hypoxia-inducible factors (HIFs), key regulators of cellular adaptation to hypoxic conditions. In the present study, we have therefore investigated the roles of HIF-1 and HIF-2 in RPE cell death in a human RPE cell line under hypoxidative stress. For this purpose, we conducted siRNA-mediated knockdowns of the α-subunits of HIF-1 and HIF-2. We found that especially iron metabolism, in particular the expression of transferrin receptor 1 (TFR1) was affected by HIF-1α silencing, resulting in decreased intracellular iron levels and ferroptosis susceptibility. We also found that heme oxygenase 1 (HO-1) contributed to cell death by hypoxidative stress. In addition, we also observed that cell metabolism was improved by HIF-1α silencing under hypoxia, most likely contributing to the protective effect. Furthermore, we identified an FDA-approved small molecule inhibitor, Vorinostat, to downregulate HIF-1α, TFR1, and HO-1 and improve cell metabolism, which eventually resulted in a full rescue of RPE cells from hypoxidative stress-induced cell death. In conclusion, this study highlights the importance of considering targeted HIF inhibition as a promising approach to protect RPE cells from degeneration.
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000303645 7001_ $$aLobo Barbosa da Silva, Maria Eduarda$$b1
000303645 7001_ $$aAmbrock, Tabea$$b2
000303645 7001_ $$00009-0003-9280-6393$$aTerosian, Orbel$$b3
000303645 7001_ $$00000-0001-5199-5472$$aMalyshkina, Anna$$b4
000303645 7001_ $$aPadberg, Claudia$$b5
000303645 7001_ $$00000-0001-5245-2373$$aLarafa, Safa$$b6
000303645 7001_ $$00000-0003-4878-8741$$aMatschke, Johann$$b7
000303645 7001_ $$aFandrey, Joachim$$b8
000303645 7001_ $$00000-0002-0166-2204$$aHenning, Yoshiyuki$$b9
000303645 773__ $$0PERI:(DE-600)2842546-7$$a10.1038/s41420-025-02675-7$$gVol. 11, no. 1, p. 380$$n1$$p380$$tCell death discovery$$v11$$x2058-7716$$y2025
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